Pharmaceutical composition comprising rotigotine salts (acid or na), especially for iontophoresis

ABSTRACT

The present invention relates to new salts of 6-(propyl-(2-thiophen-2-ylethyl)amino)tetralin-1-ol (rotigotine), their use as a medicament, for example for the treatment of CNS disorders like Parkinson Disease, RLS, fybromyalgia and/or depression, in particular through electromotive administration. The present invention relates to pharmaceutical formulations suitable for iontophoresis that provide enhanced iontophoretic delivery of rotigotine to at least one target tissue. The formulations are further characterized by good to excellent solubility of the salts in aqueous solutions.

FIELD OF THE INVENTION

The present invention relates to new salts of6-(propyl-(2-thiophen-2-ylethyl)amino)tetralin-1-ol (rotigotine), theiruse as a medicament, for example for the treatment of Parkinson Disease,RLS, fybromyalgia and/or depression, in particular through electromotiveadministration.

In another aspect the invention relates to a device, composition andmethod for improved electrotransport delivery of rotigotine and/or itssalts respectively.

The present invention provides pharmaceutical formulations suitable foriontophoresis that provide enhanced iontophoretic delivery of rotigotineto at least one target tissue. The formulations are furthercharacterized by good to excellent solubility of the salts in aqueoussolutions. The present invention also provides methods of administeringrotigotine in at least one target tissue of and/or treating one of thediseases mentioned above in a patient by iontophoretically delivering aformulation of the invention.

The present invention relates to pharmaceutical compositions comprisingat least one acid addition salt of rotigotine and the use thereof, inparticular for the use in a iontophoretic delivery system. It furtherrelates to the use of these acid addition salts of rotigotine for thetreatment of CNS disorders like Parkinson's Disease, and/or restless legsyndrome. It further relates to new rotigotine acid addition salts, inparticular rotigotine dihydrogen phosphate.

BACKGROUND OF INVENTION

Rotigotine is the International Non-Proprietary Name (INN) of thecompound(−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]-1-naphthalenol,having the structure shown below

Rotigotine is a non-ergolinic D1/D2/D3 dopamine agonist that resemblesdopamine structurally and has a similar receptor profile but a higherreceptor affinity.

In contrast to other non-ergolinic dopamine agonists, rotigotine hassignificant D1 activity, which may contribute to a more physiologicalaction.

In contrast to ergolinic compounds, rotigotine has a very low affinityfor 5 HT₂B receptors and thus a low risk of inducing fibrosis. Actionson non-dopaminergic receptors (such as 5-HT₁A agonism and A_(2B)antagonism) may contribute to other beneficial effects, such asantidyskinetic activity, neuroprotective activity and antidepressiveeffects.

Rotigotine is disclosed as active agent for treating patients sufferingfrom Parkinson's disease (WO 2002/089777), Parkinson's plus syndrome (WO2005/092331), depression (WO 2005/009424) and the restless-legs syndrome(WO 2003/092677) as well as for the treatment or prevention ofdopaminergic neurone loss (WO 2005/063237).

Rotigotine has been tested in the form of its free base or as rotigotinehydrochloride.

The Restless Leg Syndrome (RLS) is a neurological disease that expressesitself as a false sensation in the legs accompanied by a strong kineticurge. Symptoms of RLS include tingling, pulling, aching, itching,burning, cramps or pain, causing in the person concerned theirresistible urge to move. This disorder occurs most frequently when theperson concerned is resting. Therapy studies have revealed a diversityof results obtained in monotherapeutic treatments with dopamineagonists, opiates, benzodiazepines, carbamazepine, clonidine or levodopa(L-DOPA) in combination with a dopa decarboxylase inhibitor. The use ofL-DOPA for treating RLS has been the subject of a particularly largenumber of papers. Long-term L-DOPA therapy leads to a clear mitigationof the disorder with an improved quality of sleep and life. The drawbackof most conventional monotherapies is that, depending on the duration ofthe therapy, the amount of the active ingredient must be progressivelyincreased in order to ensure the success of the treatment. A surprisingdiscovery has shown that the monotherapeutic administration of arotigotine-containing transepicutaneous composition especially when inthe form of a patch composition leads to the suppression and reductionof the RLS symptoms, with rotigotine as the active substance.

Parkinson's disease is believed to be primarily caused by thedegeneration of dopaminergic neurons in the substantia nigra.Parkinson's disease is primarily a disease of middle age and beyond, andit affects both men and women equally. The highest rate of occurrence ofParkinson's disease is in the age group over 70 years old, whereParkinson's disease exists in 1.5 to 2.5% of that population. The meanage at onset is between 58 and 62 years of age, and most patientsdevelop Parkinson's disease between the ages of 50 and 79. There areapproximately 800,000 people in the United States with Parkinson'sdisease. The clinical diagnosis of Parkinson's disease is based on thepresence of characteristic physical signs. The disease is known to begradual in onset, slowly progressive, and variable in clinicalmanifestation. Evidence suggests that the striatal dopamine contentdeclines to 20% below levels found in age-matched controls beforesymptoms occur.

Treatment of Parkinson's disease has been attempted with, inter alia,L-dopa (levodopa), which still is the gold standard for the therapy ofParkinson's disease. Levodopa passes the blood-brain barrier as aprecursor for dopamine and is then converted into dopamine in the brain.L-dopa improves the symptoms of Parkinson's disease but may cause severeside effects. Moreover, the drug tends to lose its effectiveness afterthe first two to three years of treatment. After five to six years, only25% to 50% of patients maintain improvement. Furthermore a majordrawback of currently utilized therapies for Parkinson's disease is theeventual manifestation of the “fluctuation syndrome”, resulting in“all-or-none” conditions characterized by alternating “on” periods ofmobility with dyskinesias and “off” periods with hypokinesia orakinesia.

Patients who display unpredictable or erratic “on-off” phenomena withoral anti-Parkinson therapy have a predictable beneficial response to i.v. administration of L-dopa and other dopamine agonists, suggesting thatfluctuations in plasma concentrations of drug are responsible for the“on-off” phenomena. The frequency of “on-off” fluctuations has also beenimproved by continuous infusions of the dopamine receptor agonistsapomorphine and lisuride. However, this mode of administration isinconvenient. Therefore, other modes of administration providing a moreconstant plasma level, such as topical administration, are beneficialand have been suggested in the past.

Transdermal drug delivery is an alternative for oral drug delivery andhypodermic injections. Different delivery methods have been investigatedover the years to increase the drug delivery through the skin.Transdermal delivery is a well-established method of drug administrationwhereby the hepatic first-pass effect is circumvented. Several studiesinto the transdermal delivery of rotigotine have been carried out. Theresults showed a significant increase in bioavailability in comparisonto oral delivery and providing a continuous delivery pattern.Monotherapy of rotigotine via passive diffusion controlled transdermalapplication is however limited by the skin permeability and may requiredose titration to meet individual therapeutic needs. To date, varioustransdermal therapeutic systems (TTS) for the administration ofrotigotine have been described.

WO 94/07468 discloses a transdermal therapeutic system containingrotigotine hydrochloride as active substance in a two-phase matrix whichis essentially formed by a hydrophobic polymer material as a continuousphase and a disperse hydrophilic phase contained therein and mainlycontaining the drug and hydrated silica. The silica enhances the maximumpossible loading of the TTS with the hydrophilic salt.

Moreover, the formulation of WO 94/07468 usually contains additionalhydrophobic solvents, permeation-promoting substances, dispersing agentsand, in particular, an emulsifier which is required to emulsify theaqueous solution of the active principle in the lipophilic polymerphase. A TTS, prepared by using such a system, has been tested inhealthy subjects and Parkinson patients. The average drug plasma levelsobtained by using this system were around 0.15 ng/mL with a 20 cm² patchcontaining 10 mg rotigotine hydrochloride. This level is considered toolow to achieve a truly efficacious treatment or alleviation of thesymptoms related to Parkinson's Disease.

Various further transdermal therapeutic systems (TTS) have beendescribed for example in WO 99/49852. The TTS comprises a backing layer,inert with respect to the constituents of the matrix, a self-adhesivematrix layer containing an effective quantity of rotigotine orrotigotine hydrochloride and a protective film which is to be removedbefore use. The matrix system is composed of a non-aqueous polymeradhesive system, based on acrylate or silicone.

In the transdermal delivery system (TDS, which is used synonymous forTTS) according to WO94/07468 and many related applications, the drugcrosses the membrane by passive diffusion. A disadvantage of these typesof transdermal administration is that there is very limited dosingflexibility available, e.g. in view of individual dosing, limitedmaximum daily dose, on demand application, continuous or pulsatileadministration pattern, period of administration.

However, as the skin is to be seen as a very efficient barrier for mostdrug candidates, such type of membrane controlled systems are more orless limited in practice to transdermal delivery of active substancesthat reveal a very high skin permeability. Additionally, specialrequirements on drug release kinetics have to be met like contactdelivery over several days. The rotigotine flux obtained with thesepassive transdermal therapeutic systems is not necessarily sufficientfor all patients.

Different delivery methods have been investigated over the years toincrease the drug delivery through the skin.

There have been several attempts to increase the rates of transdermaldrug delivery by using of alternative energy sources such as electricalenergy and ultrasonic energy. Electrically assisted transdermal deliveryis also referred to as electro transport. The term “electro transport”or “electromotive administration” as used herein refers generally to thedelivery of an agent (e.g. a drug) through a membrane, such as skin,mucous membrane, or nails. One of the possibilities is iontophoresis. Byapplying a small current across the skin it is possible to enhance thetransdermal delivery of small charged ionic molecules. Iontophoresisinvolves the application of an electromotive force to drive or repelions through the dermal layers into a target tissue. Particularlysuitable target tissues include those adjacent to the delivery site forlocalized treatment. Uncharged molecules can also be delivered usingiontophoresis via a process called electroosmosis. This technology of“electro transport” offers several advantages over e.g. oral andinjection or passive transdermal drug delivery. Key advantages ofionthophoretic drug delivery include the avoidance of pain and potentialfor infection associated with needle injection, the ability to controlthe rate of drug delivery, the ability to programme the drug-deliveryprofile and the minimisation of local tissue trauma. One of theinteresting properties of this technique is the possibility to modulatethe transport rate into and through the skin. This is an importantadvantage for drugs with a narrow therapeutic window, such as dopamineagonists.

Iontophoretic transdermal delivery relates to introducing ions orsoluble salts of pharmaceutically active compounds into tissues of thebody under the influence of an applied electric field.

In certain cases, e.g., when transdermal delivery by means of passivediffusion controlled patches appears to be ineffective or unacceptablebecause of low passage through the skin, leading to very large patches,iontophoretic transdermal delivery may provide an advantageous method ofdelivering that compound. Further iontophoretic transdermal delivery hasthe major advantage that the administered amount can be regulatedprecisely and can be used to easily titrate patients up to a certainlevel of administration over a period of up to several weeks.

Electrotransport devices use at least two electrodes that are inelectric contact with some portion of the skin, nails, mucous membrane,or other surface of the body. One electrode, commonly called the “donor”electrode, is the electrode from which the agent is delivered into thebody. The other electrode, typically termed the “counter” electrode,serves to close the electrical circuit through the body. For example, ifthe agent to be delivered is positively charged, i.e., a cation, thenthe anode is the donor electrode, while the cathode is the counterelectrode which serves to complete the circuit. Alternatively, if anagent is negatively charged, i.e., an anion, the cathode is the donorelectrode and the anode is the counter electrode. Additionally, both theanode and cathode may be considered donor electrodes if both anionic andcationic agent ions, or if uncharged dissolved agents, are to bedelivered. Furthermore, electrotransport delivery systems generallyrequire at least one (drug) reservoir or source of the agent to bedelivered to the body.

Iontophoresis is well established for use in transdermal drug delivery.The advantage of this method is that unlike transdermal patches, itrelies on active transportation within an electric field. It allows thedelivery of water-soluble ionic drugs that are not effectively absorbedthrough the skin. In the presence of an electric field electromigrationand electroosmosis are the dominant forces in mass transport. Thesemovements are measured in units of chemical flux, commonly μmol/cm²h.There are a number of factors that influence iontophoretic transportincluding skin pH, drug concentration and characteristics, ioniccompetition, molecular size, current voltage, time applied and skinresistance.

The advantage of this technique (e.g. iontophoresis) is that the fluxcan be accurately controlled and manipulated by the externally appliedcurrent. The level of enhancement that can be achieved is, for a largepart, dependent on the charge, the lipophilicity, and the molecularweight of the drug. Compounds that enhance the percutaneous penetrationof a drug have been applied widely in passive transdermal studies,although the applicability of these compounds in humans is limited bythe level of skin irritation that they may evoke. Iontophoresis is atechnique that allows movement of ions of soluble salts across amembrane under an externally applied potential difference that isinduced across the skin by a low-voltage electric current. Theapplication of current is controlled by an electronic device thatadjusts the voltage in response to the changes in skin electricalresistance. Charged drug as well as other ions are carried across theskin as a component of induced ion flow. Numerous factors affectiontophoretic delivery, including flux proportionality with respect toapplied current density and the presence of ions other than drug.Current up to 0.5 mA/cm² is believed to be tolerable for patients. Theonset of action with iontophoretic treatment is rapid, in contrast tohours for passive transdermal delivery. Since drug delivery isproportional to applied current, significant advantages of iontophoresisinclude the possibility of preprogramming the drug delivery, dosetailoring on an individual basis, or time tailoring in a constant orpulsatile fashion.

Compared to passive transdermal delivery, iontophoresis provides forseveral advantages which are useful in the treatment of Parkinson'sdisease: it allows programming of the flux at the required therapeuticrate by adjusting the electric current. It is advantageous for a patientin need of a drug that the drug amount can be adjusted to the individualneed. Another advantage is that iontophoresis allows for continuous aswell as pulsatile administration and it permits a rapid start ortermination of administration of the medication, if needed, by simplyturning the iontophoretic delivery system on or off.

It is advantageous that control of the rate and duration of drugdelivery can be handled in a way to avoid the potential risk of overdoseand the discomfort of an insufficient dosage.

However, in any given electro transport process, more than one process,including at least some “passive” diffusion, may be occurringsimultaneously to a certain extent. Accordingly, the term “electrotransport” or “electromotive administration”, as used herein, should begiven its broadest possible interpretation so that it includes theelectrically induced or enhanced transport of at least one agent, whichmay be charged, uncharged, or a mixture thereof, whatever the specificmechanism or mechanisms by which the agent actually is transported. Forexample the total iontophoretic flux consists of the passive flux(J_(pass)), the electro-osmotic flux (J_(EO)) and the electromigrativeflux (J_(EM)). The latter two are representing the iontophotetic flux.

Another dopamine agonist which has been used in the treatment ofParkinson's disease is R-apomorphine. R-apomorphine is the InternationalNon-Proprietary Name (INN) of the compound(R)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzoquinoline-11,12-diol. Severalapproaches to develop a system for iontophoretic administration ofR-apomorphine have previously been described (see for example R. van derGeest, M. Danhof, H. E. Bodde “Iontophoretic Delivery of Apomorphine: InVitro Optimization and Validation”, Pharm. Res. (1997), 14, 1797-1802;M. Danhof, R. van der Geest, T. van Laar, H. E. Bodde, “An integratedpharmacokinetic-pharmacodynamic approach to optimization ofR-apomorphine delivery in Parkinson's disease”, Advanced Drug DeliveryReviews (1998), 33, 253-263). However, in spite of these efforts, onlyconcentrations at the lower end of the therapeutic concentration rangeof 1.4 to 10.7 ng/ml could be obtained.

A further dopamine antagonist is ropinirole hydrochloride. Ropinirole(INN) is (4-[2-dipropylamina) ethyl]-1,3-dihydro-2H-indol-2-one).Although the iontophoretic administration of ropinirole was consideredfeasible, it was only possible to obtain fluxes at the lower end of thetherapeutic range (see A. Luzardo-Alvarez, M. B. Delgado-Charro, J.Blanco-Mendez, “Iontophoretic Delivery of Ropinirole Hydrochloride:Effect of Current Density and Vehicle Formulation”, PharmaceuticalResearch (2001), 18 (12), 1714-1720).

WO2004/050083 relates to a method for treating or alleviating symptomsof Parkinson's disease, which uses iontophoretic delivery of thedopamine receptor agonist rotigotine. The composition used in theiontophoretic delivery system comprises rotigotine in form of itshydrochloride salt and at least one chloride salt in a concentration of1 to 140 mmol/l the composition having a pH of 4 to 6.5. For an optimalperformance a concentration of at least 0.5 mg/ml of the rotigotinehydrochloride is preferred, as derived from Example 1 and 2 of theEuropean patent.

Although, investigating the transdermal iontophoretic delivery ofrotigotine.HCl revealed that by applying an electrical current acrossthe skin higher steady state fluxes can be achieved with a shorter lagtime compared to passive delivery in these studies the maximumsolubility of rotigotine.HCl in the donor phase appeared to be thelimiting factor for its iontophoretic transport through the skin. It hasbeen tried to increase the solubility of rotigotine by changing thedonor solution, e.g. by adding surfactants or co-solvents or changingthe source of Cl⁻ ions. A disadvantage of this iontophoretic deliverysystem is that e.g. an increase of sodium chloride concentration resultsin a decrease of the rotigotine flux.

A further limiting factor is the limited solubility of rotigotinehydrochloride in aqueous solvents as well as the strong salting outeffect of e.g. sodium chloride.

Many patients need concentrations that are significantly higher than theones feasible using iontophoretic delivery of the above mentionedcompositions and/or are in need for an administration for a longer timeperiod.

There is still a need to develop a transdermal delivery system providingon one hand a greater dosing flexibility (e.g. individual dosing) and onthe other hand allowing continuous as well as pulsatile administration,if suitable for an extended period of time.

An object of the present invention is to control (i.e. tocanalise/manoeuvre) the transport of rotigotine towards and across theskin from a drug reservoir, thereby optimizing the administration of theindividual amount of rotigotine needed by the patient, enhancing theflux of rotigotine across the TDS/skin interface.

Another object and aspect of the present invention is to provide asuitable composition which lead to an enhanced delivery of rotigotine toand across the skin over a period of at least 24 hours, preferablylonger than 24 hours.

Another object of the present invention is to provide a continuous aswell as pulsatile delivery of the active compound across.

SUMMARY OF THE INVENTION

The present invention relates to iontophoretic transdermal technologythat provides for the delivery of pharmaceutically acceptable rotigotinesalts and compositions thereof through human skin.

The present invention provides pharmaceutical formulations suitable foriontophoresis that provide enhanced iontophoretic delivery of rotigotineto at least one target tissue. The formulations are furthercharacterized by good to excellent solubility of the salts in aqueoussolutions. The present invention also provides methods of administeringrotigotine in at least one target tissue of and/or treating one of thediseases mentioned above in a patient by iontophoretically delivering aformulation of the invention.

The present invention provides a pharmaceutical formulation comprisingat least one pharmaceutically acceptable acid addition salt of6-(propyl-(2-thiophen-2-ylethyl)amino)tetralin-1-ol (rotigotine) andoptionally a pharmaceutically acceptable electrolyte wherein saidrotigotine salt has a saturation solubility in an aqueous solution whichis at least 16 μmol/ml at a pH<6 and/or of at least 30 μmol/ml at apH≦5.5, wherein all the above saturation solubilities are calculatedbased on the total amount of rotigotine in the pharmaceuticallyacceptable acid addition salt, with the proviso that the at least onepharmaceutically acceptable acid addition salt of rotigotine is notrotigotine.HCl.

The present invention further provides new pharmaceutically acceptablesalts of rotigotine, like rotigotine dihydrogen phosphate, rotigotinedihydrogen citrate, rotigotine orotate, rotigotine1-hydroxy-2-naphtoate, rotigotine hydrogen sulfate, rotigotine hydrogentartrate, rotigotine sodium.

Surprisingly it has been found that due to an increase in the maximumsolubility of pharmaceutically acceptable rotigotine salts, inparticular rotigotine dihydrogen phosphate (rotigotine.H₃PO₄), ansubstantial increase in maximum flux, compared to rotigotine.HCl, can beachieved, that can be maintained for at least 24 hours, facilitating itsapplication. In case of rotigotine dihydrogen phosphate the increase inthe maximum solubility of rotigotine.H₃PO₄, a 170% increase in maximumflux, compared to rotigotine.HCl, was achieved, that can be maintainedfor at least 24 h, facilitating its application. A balance betweensolubility and delivery efficiency can be achieved by choosing the donorpH for example between 5 and 6. With ionthoporesis therapeutic levelscan be achieved with a rapid onset time and maintained in a controlledmanner by adjusting the current density.

It is further suprising that in one embodiment in contrast to thesolubility of the rotigotine.HCl the presence of NaCl did not affect thesolubility of the rotigotine salts of the present invention, e.g.rotigotine.H₃PO₄.

The present invention provides further two very important benefits ofiontophoretic delivery of rotigotine in combination with iontophoresisover transdermal passive diffusion for symptomatic treatment of e.g.Parkinson's disease. Because of active transdermal delivery the onsettime to achieve the desired level can be significantly decreased.Secondly by adjusting the current density a titration of the plasmaconcentration is possible, making it feasible to individually modulatethe delivery according to the desired dosing regimen.

Using the parameters, determined by modeling the in vitro transport, invivo simulations revealed that with iontophoresis therapeutic levels canbe achieved with a rapid onset time and be maintained in a controlledmanner by adjusting the current density.

Fluxes of around 50 μg/cm²/hr can be achieved. A linear relationshipbetween iontophoresis (steady state flux) and current density wasobtained, which allows individual dose titration into the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an exemplarily design of the iontophoresis cell.

FIG. 2 is a graph showing iontophoretic steady state flux±s.d. ofrotigotine versus drug concentration.

FIG. 3 shows iontophoretic flux time profile of Rotigotine.H₃PO₄dissolved in citric buffer pH 5.

FIG. 4 shows the correlation of the Flux_(ss) during the passive phase(no current) and the iontophoretic phase (current density=500 μA·cm⁻²)versus the donor concentration at different pHs.

FIG. 5 shows combined impact of donor solution pH and drug concentrationon passive and iontophoresis transdermal steady state flux of rotigotine

FIG. 6 shows impact of current density on transdermal steady state drugflux from donor solutions.

FIG. 7 is a graph showing population prediction of the simulations ofiontophoretic delivery of rotigotine.H₃PO₄

FIG. 8 shows a powder X ray diffractogram (XRPD) of rotigotinedihydrogen phosphate

FIG. 9 shows a ¹H NMR spectra of rotigotine dihydrogen phosphate.

FIG. 10 shows a XRPD of rotigotine dihydrogen citrate

FIG. 11 shows a ¹H NMR spectra of rotigotine dihydrogen citrate.

FIG. 12 shows a ¹H NMR spectra of rotigotine hydrogen tartrate.

FIG. 13 shows a ¹H NMR spectra of rotigotine orotate.

FIG. 14 shows a XRPD of rotigotine orotate.

FIG. 15 shows a ¹H NMR spectra of rotigotine 1-hydroxy-2-naphtoate

FIG. 16 shows a XRPD of rotigotine 1-hydroxy-2-naphtoate

FIG. 17 shows a DSC of rotigotine 1-hydroxy-2-naphtoate

FIG. 18 shows a XRPD of rotigotine hydrogen sulphate

FIG. 19 shows a ¹H NMR spectra of rotigotine hydrogen sulphate

FIG. 20 shows a ¹H NMR spectra of rotigotine sodium

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to new salts of6-(propyl-(2-thiophen-2-ylethyl)amino)tetralin-1-ol which is synonymouswith the term rotigotine,

In one aspect, the invention provides pharmaceutical formulations thatare suitable for iontophoresis and that provide enhanced iontophoreticdelivery of rotigotine to a patient, preferably a human patient, in needof treatment.

Thus, the invention relates to the iontophoretic delivery of rotigotine,including cathodal or anodal iontophoresis.

The present invention also relates to the use of compounds of thegeneral formula I for the preparation of (a) a formulation for use in adevice for transdermal administration by iontophoresis or kitscontaining cartridges which contain the compound ready for use in saiddevice, (b) a device suitable for transdermal administration byiontophoresis, wherein said transdermal device has a reservoircontaining the compound of formula I or a composition thereof andoptionally a pharmaceutically acceptable electrolyte, which device canbe used in a method for controlling the delivery profile ofpharmaceutical compounds of the general formula I and compositionsthereof, and the use of said controlled delivery profiles in thetreatment of pain disorders, especially CNS disorders, especiallyParkinson's disease, and restless leg syndrome.

Since rotigotine is a base, the salts of rotigotine are typically acidaddition salts, e.g., citrate salts, phosphate salts, etc. The acidaddition salts of rotigotine used in the formulations of the presentinvention typically have water solubilities of at least about 16 μmol/mlat a pH<6 and/or of at least about 30 μmol/ml at a pH≦5, wherein all theabove saturation solubilities are calculated based on the total amountof rotigotine in the pharmaceutically acceptable acid addition salt. Theacid addition salt of rotigotine dihydrogen phosphate typically has awater solubility of about 83 to 34 μmol/ml in a pH range of about 4 to5.5. When the salts are placed in solution (e.g. aqueous solution), thesalts dissolve and form protonated rotigotine cations and counter (e.g.,citrate or phosphate) anions. As such, the rotigotine cations aredelivered from the anodic electrode of an electrotransport deliverydevice.

In one embodiment, the concentration of the active agent, calculated asfree base of rotigotine, in the formulation is at least about 16 μmol/mlof rotigotine at a pH<6, and/or such as at least about 30 μmol/ml ofrotigotine at a pH≦5. In another embodiment the concentration of theactive agent, calculated as free base of rotigotine, in the formulationis at least about 50 μmol/ml of rotigotine at a pH≦4

Where particular values are described in the application and claims,unless otherwise stated the term “about” means within an acceptableerror range for the particular value as determined by one of ordinaryskill in the art. In one embodiment, the term “about” means ±10%, inanother one ±5%, another one ±2%, another one ±1%, or another one ±0.5%.

One object of the present invention is to provide compounds of generalformula I

wherein X^(n−) is the acid anion of a pharmaceutically acceptableinorganic or organic acid with the proviso that it is notrotigotine.HCl. The present invention relates to compounds of generalformula I wherein X^(n−) comprises mono and/or poly valent anions. Thereare certain acids having more than one acid protons which can besalified. For example citric acid has three carboxyl groups, all or partof which can be salified by the rotigotine base. Thus the formulation ofthe present invention can comprise monorotigotine dihydrogen citrate,dirotigotine hydrogen citrate or trirotigotine citrate or mixed citratesof rotigotine. The same applies to other acids addition salts liketartrates, sulfates, phosphates etc.

It is to be understood that each individual atom present in formula (I),or in the formulae depicted hereinafter, may in fact be present in theform of any of its naturally occurring isotopes, with the most abundantisotope(s) being preferred. Thus, by way of example, each individualhydrogen atom present in formula (I), or in the formulae depictedhereinafter, may be present as a ¹H, ²H (deuterium) or ³H (tritium)atom, preferably ¹H. Similarly, by way of example, each individualcarbon atom present in formula (I), or in the formulae depictedhereinafter, may be present as a ¹²C, ¹³C or ¹⁴C atom, preferably ¹²C.This does also apply to rotigotine in form of its free base

For a skilled person the term(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-oltartrate (rotigotine tartrate) is synonymous with the term dirotigotinetartrate,(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-olcitrate (rotigotine citrate) is synonymous with the term trirotigotinecitrate and(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-olphosphate is synonymous with the term trirotigotine phosphate—if notstated otherwise.

Representative acid addition salts include, but are not limited to,acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrobromide, hydroiodide, 2-hydroxyethansulfonate(isothionate), 1-hydroxy-naphtoate, lactate, maleate, mesylate, methanesulfonate, nicotinate, 2-naphthalene sulfonate, orotate, oxalate,palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, phosphate, succinate, tartrate, thiocyanate,phosphate, glutamate, bicarbonate, p-toluenesulfonate and sulphate, allof the foregoing comprising all variations from partly salified tocompletely salified.

In one embodiment the acid addition salt is not(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-olhydrobromide,(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-olp-toluensulfonate,(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-olheminaphthalene-1,5-disulfonate,(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-oltartrate, and(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-olphosphate.

In another embodiment the acid addition salt is further not(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-olcitrate,(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-olsulfate and(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-olmethanesulfonate.

More specifically the invention is related to pharmaceutical compoundsof the general formula I selected from dirotigotine hydrogen phosphate,rotigotine dihydrogen phosphate, rotigotine dihydrogen citrate,dirotigotine hydrogen citrate, rotigotine orotate, rotigotine1-hydroxy-2-naphtoate, rotigotine hydrogen sulfate, rotigotine sulphate,rotigotine hydrogen tartrate or mixtures thereof.

In another embodiment the acid addition salt is selected from rotigotinedihydrogen phosphate, rotigotine dihydrogen citrate, rotigotine orotate,rotigotine 1-hydroxy-2-naphtoate, rotigotine hydrogen sulphate,rotigotine hydrogen tartrate or mixtures thereof.

Even more specifically the invention is related to the use of at leastone compound of the general formula I as defined above, or mixturesthereof, for the manufacture of an medicament for the treatment offybromyalgia, restless leg syndrome and CNS disorders, especiallyParkinson's disease.

The present invention relates to transdermal iontophoretic delivery ofpharmaceutical compounds of general formula I wherein X^(n−) comprisesmono and/or poly valent anions. More specifically the invention isrelated to transdermal iontophoretic delivery of pharmaceuticalcompounds of the general formula I wherein the salt⁻ is dirotigotinehydrogen phosphate, rotigotine dihydrogen phosphate, rotigotinedihydrogen citrate, dirotigotine hydrogen citrate, rotigotine orotate,rotigotine 1-hydroxy-2-naphtoate, rotigotine hydrogen sulfate,rotigotine sulphate, rotigotine hydrogen tartrate, rotigotine tartrateor mixtures thereof.

In one embodiment of transdermal iontophoretic delivery ofpharmaceutical compounds of general formula I, X^(n−) is selected fromthe acid anion of methane sulphonic acid, benzene sulphonic acid,phosphoric acid, tartaric acid, gluconic acid, citric acid, malic acid,lactic acid, benzoic acid, adipic acid, maleic acid, aspartic acid,fumaric acid, succinic acid, sulphuric acid, orotic acid,1-hydroxy-naphtoic acid. In another embodiment X⁻ is selected from theacid anion of phosphoric acid, sulphuric acid, orotic acid,1-hydroxy-naphtoic acid, citric acid, tartaric acid, in particulardihydrogen phosphate.

As stated above, the compounds of formula I can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. Salts of prodrugs also fall within the scope of this invention.The phrase “pharmaceutically acceptable salt” means those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting a free base function with a suitableorganic acid.

These compounds are suitable for use as a medicament in particular fortreating CNS disorders like Parkinson Disease, fibromyalgia, restlessleg syndrome, depression and/or Parkinson's accessory symptoms. They aresuitable for use in a transdermal delivery system. Such transdermaldelivery system can for example be a patch, an electro transport device,inotophoretic delivery system.

One object of the present invention is to provide stable salts ofrotigotine with improved solubilities in solutions at a pH of less than6. Rotigotine as the free base has high solubility in common organicsolvents, but low solubility in water.

Under the conditions according to the present invention it is possibleto maintain a pharmaceutical composition with a higher concentration ofan effective amount of rotigotine without the need of further addingsalt(s) (ions), e.g. chloride salts. A disadvantage of the systems knownin the art is a salting out effect which decreases the availablerotigotine transport through the skin. In previous attempts one of themajor limitations in the iontophoretic transport of rotigotine.HCl wasits low solubility. For example the maximum solubility of rotigotine.HClwas only 22.4 μmol/ml (in absence of further chloride salts) at pH 5 andin the presence of 0.07 molar NaCl the maximum solubility ofrotigotine.HCl decreased to 6.3 μmol/ml at pH 5. In that study theiontophoretic transport at varying rotigotine.HCl concentrations between1.4 and 3.9 μmol/ml showed a linear relationship between the Flux_(ss)and the donor concentration. This demonstrated that the maximumiontophoretic flux of rotigotine was not yet achieved, but the lowsolubility of rotigotine.HCl prevented further increase in theiontophoretic flux.

The solubility of rotigotine is an important determinant of the maximumdrug concentration. The problem of a rotigotine acid addition salthaving a maximum solubility in an aqueous solution at a pH of about 6 ofless than 16 μmol/ml or having a maximum solubility in an aqueoussolution at a pH of about 5.5 of less than 30 μmol/ml (calculated basedon the total amount of rotigotine in the pharmaceutically acceptableacid addition salt) like rotigotine.HCl is that their use for electrotransport is limited due to a low or poor iontophoretic transportationrate. Another disadvantage is the negative impact of the addition ofchloride salts on solubility of rotigotine.HCl and therefore on theavailable rotigotine concentration available for skin permeation.

Surprisingly, it was found that certain acid addition salts ofrotigotine are more soluble than the rotigotine hydrochloride salt formand are thus particularly suited for pharmaceutical compositions for usein transdermal electrotransport, e.g. iontophoresis. Suitable rotigotinesalts for transdermal electrotransport are for example the onesmentioned herein. In one embodiment the salts are selected from theorotate, citrate (including hydrogen citrate, dihydrogen citrate)tartrate (including hydrogen tartrate, tartrate), phosphates (includingdihydrogen phosphate, hydrogen phosphate and phosphate) of rotigotine.In one embodiment the salt is selected from the hydrogen sulfate,orotate, dihydrogen citrate, hydrogen tartrate, in particular hydrogenL-tartrate and/or dihydrogen phosphate of rotigotine. In anotherembodiment the salt is selected from the orotate, hydrogen tartrate, inparticular hydrogen L-tartrate and/or dihydrogen phosphate ofrotigotine. In still another embodiment the pharmaceutically acceptablesalt is rotigotine dihydrogen phosphate which has the formula:

One embodiment comprises a pharmaceutical formulation comprising atleast one pharmaceutically acceptable acid addition salt of6-(propyl-(2-thiophen-2-ylethyl)amino)tetralin-1-ol (rotigotine) andoptionally a pharmaceutically acceptable electrolyte wherein saidrotigotine salt has a saturation solubility in an aqueous solution whichis at least about 16 μmol/ml at a pH<6 wherein all the above saturationsolubilities are calculated based on the total amount of rotigotine inthe pharmaceutically acceptable acid addition salt, with the provisothat the at least one pharmaceutically acceptable acid addition salt ofrotigotine is not rotigotine.HCl, in particular a pharmaceuticalcomposition comprising at least rotigotine dihydrogen phosphate as arotigotine acid addition salt. In another embodiment the pharmaceuticalcomposition comprises at least one pharmaceutically acceptable acidaddition salt of rotigotine characterized in that the at least onepharmaceutically acceptable acid addition salt of rotigotine has asaturation solubility in an aqueous solution which is at least about 30μmol/ml at a pH≦5.5, in particular a pharmaceutical compositioncomprising at least rotigotine dihydrogen phosphate. In anotherembodiment the pharmaceutical composition comprises at least onepharmaceutically acceptable acid addition salt of rotigotinecharacterized in that the at least one pharmaceutically acceptable acidaddition salt of rotigotine has a saturation solubility in an aqueoussolution which is at least about 40 μmol/ml at a pH≦5, in particular apharmaceutical composition comprising at least rotigotine dihydrogenphosphate. All the above saturation solubilities are calculated based onthe total amount of rotigotine in the pharmaceutically acceptable acidaddition salt.

Other salts which can be used in the pharmaceutical compositionsaccording to the present invention are disclosed further above and inthe claims. In one embodiment, the pharmaceutical composition comprisessaid rotigotine acid addition salt, which is not the HCl, the tartrateor the phosphate salt of rotigotine. In just another embodiment, thepharmaceutical composition comprises said rotigotine acid addition saltwhich is not the rotigotine HCl salt, for use in a transdermalelectrotransport system. Another aspect is the use of said acid additionsalts of rotigotine in the preparation of an iontophoretic device.Another aspect of the present invention is an iontophoretic devicecomprising a pharmaceutical composition as described further above.Another aspect of the invention is the use of said pharmaceuticalcompositions as described herein for the manufacturing of a transdermalmedicament or device, particularly an iontophoretic device.

The temperature range wherein the saturation solubility is provided isusually in the range of about 15-40° C. In one embodiment it is in therange of about 18-38° C. and in another one in the range of about 18-25°C.

In an embodiment, desirable solutions for iontophoresis have all drug insolution and the concentration of the drug should not be too near thedrug solubility limit. If the drug concentration is near the solubilitylimit small changes in temperature or composition can result in drugprecipitation.

In order to avoid precipitation of the at least one pharmaceuticallyacceptable salt of rotigotine in one embodiment the amount of therotigotine salt present is less than the amount necessary to achievesaturation of the solution. In another embodiment a pharmaceuticalcomposition according to invention comprises the at least onepharmaceutically acceptable salt of rotigotine in an amount of at least80% of the amount necessary to achieve saturation. In another embodimentthe amount is at least 90% of the amount necessary to achievesaturation.

In one embodiment the pH of the pharmaceutical composition is less than6, in another one pH≦5.5 and yet another one pH≦5. In another embodimentthe pH is in the range of 3 to 5.9 and in another one in the range of 4to 5.5. In one embodiment the saturation solubility of the rotigotinesalt is at least 30 μmol/ml within the range of 4 to 5.5.

The pH of the solution in the drug reservoir may be at least about 3.0in some embodiments. In other embodiments, the pH may be less than orequal to about 6. In still other embodiments, the pH may range fromabout 4.0 to about 5.9 or 6. The pH can be maintained on a constantlevel by means of a buffer such as a citrate buffer or a phosphatebuffer.

In one embodiment the pharmaceutical composition further comprises abuffer solvent. Suitable buffer solvents are all buffers which providethat the pH of the solution changes very little when a small amount ofacid or base is added within the requested pH range. This includes pHranges of 6. Suitable buffers are for example HCl, Sodium citrate,Citric acid/Sodium citrate, Acetic acid/Sodium acetate, Citricacid/Na₂HPO₄.

In one embodiment, the pharmaceutically acceptable rotigotine salt isformulated in a buffer at a pH between about 3 and 6 (preferably betweenabout 4 and 5.9) or between 5 and 6 (preferably between about 5 and5.9).

The term “buffer” refers to solutions of compounds that are known to besafe for pharmaceutical or veterinary use in formulations and that havethe effect of maintaining or controlling the pH of the formulation inthe pH range desired for the formulation.

In the drug reservoir, the concentration of the pharmaceuticallyacceptable salt of rotigotine may be, for example, is at least about 16μmol/ml at a pH<6, wherein the concentration is calculated based on thetotal amount of rotigotine in the pharmaceutically acceptable acidaddition salt, with the proviso that the at least one pharmaceuticallyacceptable acid addition salt of rotigotine is not rotigotine.HCl. Theconcentration of the rotigotine salt in the drug reservoir may be, forexample in another embodiment, at least about 30 μmol/ml at a pH 5.5 andin still another embodiment the concentration of the rotigotine salt inthe drug reservoir may be about 40 μmol/ml at a pH≦0.5.

Additionally, the drug reservoir of the iontophoretic system may includefurther additives. Such additives can be chosen from those that are wellknown and conventional in the iontophoresis art. Such additives include,for example, antimicrobial agents, preservatives, antioxidants,penetration enhancers and buffers.

It has surprisingly been found that the iontophoretic delivery (dose andprofile) by which a particular active compound of the general formula(I) is administered to a patient may be controlled by suitablecombination of the initial concentration of the drug and electrolyte andthe applied current (constant/variable) in the iontophoretic system. Forexample, it has been found that the combination of current density(constant/variable) and the initial amount of electrolyte may lead to aniontophoretic device with a very reasonable size that allows the drugdelivery profile to be adjusted.

The ability to tailor the drug delivery profile in iontophoresis mayprovide increased control of the drug's effects on the user.Additionally, the ability to tailor drug delivery profile iniontophoresis may make the iontophoretic delivery of the compounds offormula (I) a more practically effective mode of administration.

For the purposes of electromotive administration, and in particular ofiontophoretic administration, the pharmaceutically acceptable rotigotinesalt, in addition to its aqueous solution form, can also be formulatedin any form in which the rotigotine ions are free to move. In suchformulations the medicament can be incorporated into a gel (such asgelatin), a hydrogel, a gum, a foam, or a nonionic cream so as to makethe iontophoresis process convenient.

Silver anodic electrodes have been proposed for transdermalelectrotransport delivery as a way to maintain pH stability in theanodic reservoir. One of the shortcomings of using a silver anodicelectrode in an electrotransport delivery device, namely that theapplication of current through the silver anode causes the silver tobecome oxidized (Ag−>Ag<+>+e<−>) thereby forming silver cations whichcompete with the cationic drug for delivery into the skin byelectrotransport. Silver ion migration into the skin results in atransient epidermal discoloration (TED) of the skin. Therefore in someembodiments supplementary chloride ion sources like chloride salts areincluded in the formulation of the present invention. These chloridesare effective at providing sufficient chloride for preventing silver ionmigration, and the attendant skin discoloration when deliveringrotigotine transdermally by electrotransport using a silver anodicelectrode.

To feed the electrochemical reaction at the anodal side using a Ag/AgClelectrode chloride salts as electrolytes are often added to the donorsolution. Examples of suitable electrolytes include all Cl⁻ donatingcompounds that are water soluble, such as HCl, NaCl, KCl, CaCl₂, MgCl₂,triethylammonium chloride and tributylammonium chloride. In oneembodiment the suitable electrolytes include all Cl⁻ donating compoundsthat are water soluble with the proviso that it is not rotigotine.HCl.In one embodiment the electrolyte comprises NaCl. The required amount ofelectrolyte may depend on factors such as the transport area of thedevice, the volume of the vehicle or carrier, the concentration of theactive compound, the current density, the duration of the iontophoresisand the efficiency of the transport. A suitable chloride concentrationis within the range of 1 to 140 mmol/l, preferably 50 to 100 mmol/l,more preferably 60 to 80 mmol/l. In other embodiments the electrolytemay be present in amounts of, for example, at least about 0.005 mmole,at least about 0.01 mmole, or at least about 0.05 mmole. The electrolytemay be present in amounts of, for example, not more than about 2 mmole,not more than about 1.0 mmole, or not more than about 0.3 mmole. Theinitial amount of electrolyte may be expressed as a concentration of,for example, at least about 0.005 M, at least about 0.01 M, or at leastabout 0.03 M. The initial amount of electrolyte may be expressed as aconcentration of, for example, not more than about 2 M, not more thanabout 0.2 M, or not more than about 0.02 M.

The composition as described herein can be used in the donor phase of aniontophoretic device. Usually the donor phase is contained in a donorreservoir. Any conventional iontophoretic device may be used in theinvention. Such iontophoretic devices are described e.g. in V. Nair, O.Pillai, R. Poduri, R. Panchagnula, “Transdermal Iontophoresis. Part I:Basic Principles and Considerations” Methods Find. Exp. Clin. Pharmacol.(1999), 21 (2), 139-151.

The drug reservoir contains the drug and optional electrolyte with, asthe vehicle or carrier, either an aqueous solution or a (hydro) gel. Thereservoir gel may be comprised of water soluble polymers or hydrogels.In principle any gel can be used.

The composition according to the present invention is mostly used in thedonor phase of the iontophoretic device.

In some embodiments, the iontophoretic system comprises (a) atransdermal delivery device attachable to the skin, the devicecomprising a first electrode and a second electrode, and a reservoircapable of comprising a compound of the formula I as set forth above,and optionally a pharmaceutically acceptable electrolyte, in electricalcommunication with the first and second electrodes, and (b) means forconnecting an electrical power source to the first and secondelectrodes.

The iontophoretic device offers the possibility to enhance thetransdermal transport of in particular polar electrically charged drugs.In addition to increasing drug transport, iontophoresis offers thepossibility to deliver the drug in a programmed way. This is importantin the treatment of Parkinson's disease in which, due to a narrowtherapeutic window, accurate individualized dosing is crucial.Therefore, it is possible that the iontophoretic device provides apulsatile or continuous administration.

In one embodiment a pharmaceutical composition according to the presentinvention used for transdermal administration, in particular when usedfor iontophoretic administration, can be used for pulsatile as well asfor continuous administration.

In one embodiment of present invention of a pharmaceutical compositionis suitable for the treatment of Parkinson's disease, Restless Syndrome,Depression, Fibromyalgia and/or Parkinson's accessory symptoms. Inanother embodiment the pharmaceutical composition is used in aniontophoretic device for administration via electro transport for thetreatment of Parkinson Disease and/or RLS.

The formulations are preferably administered via iontophoresis. Thecurrent density employed during iontophoresis may be varied according tothe patient's needs and will depend on the iontophoretic device and thecomposition used. A suitable current may be determined by the attendantphysician. For example the current density can be at a level from about0.001 to about 1.0 mA/cm². In general, a suitable current density willbe in the range of preferably 200 to 500 μA/cm². In one embodiment thecurrent density is in the range of 250 to 400 μA/cm². In anotherembodiment the current density is in the range of 300 to 380 μA/cm².

In one embodiment, a current density of at least 150 μA/cm² is applied,in another one at least 167 μA/cm², in another one at least 300 μA/cm²,in another one at least 350 μA/cm², in another one at least 500 μA/cm².

In one embodiment, a flux of at least about 12 μg/cm²/h, in another onea flux of at least about 20 μg/cm²/h, a flux of at least about 30μg/cm²/h, a flux of at least about 40 μg/cm²/h is achieved. Theiontophoresis can be applied for a sufficient time to achieve aneffective amount of drug in the skin.

During the delivery period, the current may be caused to flow byapplying a constant or variable, such as pulsed or alternatingvoltage/current. Alternatively, the current may be caused to increaseduring the delivery period in order to titrate an increasingconcentration of the compound of formula (I).

The voltage charged in the current application step is selected in therange of voltage that does not injure the skin of a living body and thatdoes not disadvantage the rate of the transdermal absorption of theactive compound. The voltage can be, for example, at least about 0.1 V,or at least about 0.5 V, or at least about 1 V. The voltage also can be,for example, less than about 40 V, or less than about 20 V, or less thanabout 10 V.

The pulsed or alternating voltage may have a frequency of, for example,at least about 0.01 Hz, or at least about 100 Hz, or at least about 5kHz. The pulsed or alternating voltage may have a frequency of, forexample, no more than about 200 kHz, or no more than about 100 kHz, orno more than about 80 kHz. The pulsed or alternating voltage may usesubstantially any type of waveform shape, including for example, sine,square, triangular, sawtooth, rectangular, etc. In addition, the pulsedor alternating voltage may be applied on a duty cycle less than 100%.

The maximum amount of rotigotine salt that can dissolve at roomtemperature in a specific volume represents the saturation solubility ormaximum solubility which are used synonymous.

The present invention further relates to the following embodiments whichare not exhaustive:

-   1. A pharmaceutical formulation comprising at least one    pharmaceutically acceptable acid addition salt of    6-(propyl-(2-thiophen-2-ylethyl)amino)tetralin-1-ol (rotigotine) and    optionally a pharmaceutically acceptable electrolyte wherein said    rotigotine salt has a saturation solubility in an aqueous solution    which is at least 16 μmol/ml at a pH<6 and/or of at least 30 μmol/ml    at a pH≦5, wherein all the above saturation solubilities are    calculated based on the total amount of rotigotine in the    pharmaceutically acceptable acid addition salt with the proviso that    said salt is not rotigotine.HCl.-   2. A pharmaceutical formulation according to embodiment 1 wherein    the electrolyte is a chloride salt.-   3. A pharmaceutical formulation according to embodiment 2 with the    proviso that the electrolyte is not rotigotine.HCl.-   4. A pharmaceutical formulation according to any of the preceding    embodiments wherein the electrolyte is selected from NaCl, KCl,    CaCl₂, MgCl₂, triethylammonium chloride and/or tributylammonium    chloride.-   5. A pharmaceutical formulation according to any of the preceding    embodiments wherein the concentration of the chloride salt is at    least about 1 mmol/l.-   6. A pharmaceutical formulation according to any of the preceding    embodiments wherein the concentration of the chloride salt is about    1 to 140 mmol/l.-   7. A pharmaceutical formulation according to according to any of the    preceding embodiments wherein the pH of the pharmaceutical    formulation is <6.-   8. A pharmaceutical formulation according to according to any of the    preceding embodiments wherein the pH of the pharmaceutical    formulation is ≦5.-   9. A pharmaceutical formulation according to any of the preceding    embodiments comprising a solution with a pH in a range of about 4-6.-   10. A pharmaceutical formulation according to any of the preceding    embodiments wherein the saturation solubility in an aqueous solution    is provided at about 15-40° C.-   11. A pharmaceutical formulation according to any of the preceding    embodiments wherein the saturation solubility in an aqueous solution    is provided at about 18-38° C.-   12. A pharmaceutical formulation according to any of the preceding    embodiments wherein the saturation solubility in an aqueous solution    is provided at about 18-25° C.-   13. A pharmaceutical formulation according to any of the preceding    embodiments wherein the pharmaceutical formulation comprises the at    least one pharmaceutically acceptable salt of rotigotine in an    amount of less than 100% of the amount necessary to achieve    saturation.-   14. A pharmaceutical formulation according to any of the preceding    embodiments wherein the pharmaceutical formulation comprises the at    least one pharmaceutically acceptable salt of rotigotine in an    amount of at least 80% of the amount necessary to achieve    saturation.-   15. A pharmaceutical formulation according to any of the preceding    embodiments wherein the pharmaceutical formulation comprises the at    least one pharmaceutically acceptable salt of rotigotine in an    amount of at least 90% of the amount necessary to achieve    saturation.-   16. A pharmaceutical formulation according to any of the preceding    embodiments further comprising a buffer solvent.-   17. A pharmaceutical formulation according to embodiment 16 wherein    the buffer is a citrate buffer.-   18. A pharmaceutical formulation according to any of the preceding    embodiments wherein the at least one pharmaceutically acceptable    acid addition salt of rotigotine is selected from dirotigotine    hydrogen phosphate, rotigotine dihydrogen phosphate, rotigotine    dihydrogen citrate, dirotigotine hydrogen citrate, rotigotine    orotate, rotigotine 1-hydroxy-2-naphtoate, rotigotine hydrogen    sulfate, rotigotine sulphate, rotigotine hydrogen tartrate.-   19. A pharmaceutical formulation according to any of the preceding    embodiments wherein the at least one pharmaceutically acceptable    acid addition salt of rotigotine is rotigotine dihydrogen phosphate.-   20. Use of a pharmaceutical formulation according to any of the    preceding embodiments for application in a transdermal delivery    system.-   21. Use of a pharmaceutical formulation according to any of the    preceding embodiments for application in an electro transport device    for transdermal administration.-   22. Use of a pharmaceutical formulation according to any of the    preceding embodiments for application in a transdermal delivery    system wherein the system is an iontophoretic system.-   23. Use of a pharmaceutical formulation according to any of the    preceding embodiments, wherein the formulation is used in a donor    phase.-   24. Use of a pharmaceutical formulation according to embodiment 21    to 23 wherein the said device is able to deliver a constant and/or    variable current during the current application step in the    transdermal administration.-   25. Use of a pharmaceutical formulation according to embodiment 21    to 24 wherein the iontophoretic device provides a pulsatile or    continuous administration.-   26. Use of a pharmaceutical formulation according to embodiment 20    to 25 wherein the flux is at least 43 μg/cm²/h at a concentration of    at least 13 μmol/ml of the at least one pharmaceutically acceptable    acid addition salt rotigotine at a pH 6 and/or the flux is at least    47.9 μg/cm²/h at a concentration of at least 31 μmol/ml of the at    least one pharmaceutically acceptable acid addition salt rotigotine    at a pH 5.5 and/or the flux is at least 37 μg/cm²/h at a    concentration of at least 22 μmol/ml of the at least one    pharmaceutically acceptable acid addition salt rotigotine at a pH 5    wherein all the above concentrations are calculated based on the    total amount of rotigotine in the pharmaceutically acceptable acid    addition salt.-   27. Use of the of a pharmaceutical formulation according to any of    the preceding embodiments for the prevention or treatment of CNS    disorders like Parkinson's disease, Restless Legs Syndrome,    Parkinson Plus Syndrome, depression, fibromyalgia and/or Parkinson's    accessory symptoms.-   28. Compounds of general formula I

-   -   wherein X^(n−) is the acid anion of a pharmaceutically        acceptable inorganic or organic acid and wherein n is 1-5 with        the proviso that it is not rotigotine.HCl.

-   29. Compound according to embodiment 28 with the further proviso    that formula I is not    (S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol    hydrobromide,    (S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol    p-toluensulfonate,    (S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol    heminaphthalene-1,5-disulfonate,    (S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol    tartrate,    (S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol    citrate, rotigoine methane sulphonic acid and    (S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol    phosphate.

-   30. Compounds according to embodiment 28 or 29, characterized in    that X^(n−) is selected from the acid anion of, benzene sulphonic    acid, phosphoric acid, gluconic acid, citric acid, malic acid,    lactic acid, benzoic acid, adipic acid, maleic acid, aspartic acid,    fumaric acid, succinic acid, sulphuric acid, orotic acid,    1-hydroxy-naphtoic acid.

-   31. Compounds according to embodiment 28 to 30 wherein the X^(n−) is    selected from the acid anion of phosphoric acid, sulphuric acid,    orotic acid, 1-hydroxy-naphtoic acid, citric acid and/or tartaric    acid.

-   32. Compounds according to embodiment 28 to 31 wherein the compound    of formula I is rotigotine dihydrogen phosphate.

-   33. A compound of general formula II

-   -   wherein M⁺ is selected from Na⁺, K⁺ and/or arginate.

-   34. A compound according to embodiment 33 wherein M⁺ is Na⁺.

-   35. Compound according to embodiment 28 to 34 for use as a    medicament.

-   36. Compound according to any of embodiment 28 to 34 for    manufacturing a pharmaceutical product for the treatment of CNS    disorders, Parkinson Disease, fybromyalgia, restless leg syndrome,    depression and/or Parkinson's accessory symptoms.

-   37. Pharmaceutical formulation comprising a compound according to    embodiment 28 to 34.

-   38. Use of a compound according to any of embodiment 28 to 34 for    the use in a transdermal delivery system.

-   39. Use according to embodiment 38 wherein the transdermal delivery    system is a patch.

-   40. Use according to embodiment 38 wherein the transdermal delivery    system is an iontophoretic device.

-   41. Use according to embodiment 38, wherein the embodiment does not    apply to rotigotine tartrate or rotigotine phosphate.

-   42. The use of at least one compound of the general formula I or    formula II according to any of embodiments 28 to 34 or a mixture    thereof, and optionally a pharmaceutically acceptable electrolyte,    for the manufacture of an iontophoretic device for the prevention or    treatment of CNS disorders, Parkinson Disease, fybromyalgia,    restless leg syndrome, depression and/or Parkinson's accessory    symptoms.

-   43. The use according to embodiment 42, wherein said iontophoretic    device has a reservoir containing the compound of formula I or a    composition thereof or formula II or a composition thereof and    optionally a pharmaceutically acceptable electrolyte.

-   44. The use according to any of embodiments 42-43, wherein the    compound of formula I and the optional electrolyte are dissolved in    a vehicle or carrier consisting of an aqueous solution or a gel.

-   45. The use according to embodiment 43 or 44, wherein the    iontophoretic device additionally contains a membrane which    separates the vehicle or carrier from the skin when applied for    transdermal administration by iontophoresis.

-   46. The use according to embodiments 42-45, characterized in that    said iontophoretic device is able to deliver a constant current    during the current application step in the transdermal    administration by iontophoresis.

-   47. The use according to embodiments 42-46, characterized in that    said iontophoretic device is able to deliver a variable current    during the current application step in the transdermal    administration by iontophoresis.

-   48. The use according to embodiment 46 or 47, characterized in that    said iontophoretic device is able to deliver an increasing current    during the current application step in the transdermal    administration by iontophoresis.

-   49. The use according to embodiments 42-48, characterized in that    said iontophoretic device is able to deliver a current density at a    level from about 0.001 to about 1.0 mA/cm².

-   50. The use according to embodiments 49, characterized in that said    iontophoretic device is able to deliver a current density at a level    from about 200 to 500 μA/cm².

-   51. The use according to embodiments 42-50, characterized in that    said iontophoretic device is able to deliver fluxes of around 50    μg/cm²/hr.

-   52. The use according to embodiments 42-51, wherein the compound    concentration in the solution is 4.4 mM to 47.5 mM, buffered at pH 5    and/or    -   wherein the compound concentration in the solution corresponds        to concentrations rotigotine free base of 1.4 mg/ml to 15 mg/ml,        buffered at pH 5 and/or    -   wherein compound concentration in the solution is 4.4 mM to 13.5        mM, buffered at pH 6 and/or    -   wherein the compound concentration in the solution corresponds        to concentrations rotigotine free base of 1.4 mg/ml to 4.3        mg/ml, buffered at pH 6.

-   53. The use according to embodiments 42-52, wherein the compound of    formula I is rotigotine dihydrophosphate.

-   54. The use according to embodiments 42-52, wherein the compound of    formula I is rotigotine orotate.

-   55. The use according to embodiments 42-52, wherein the compound of    formula I is rotigotine hydrogen sulphate.

-   56. The use according to embodiments 42-51, wherein the compound of    formula II is rotigotine sodium salt.

-   57. The use according to embodiments 42-55 wherein the iontophoresis    is anodal and performed at a pH of less than about 6.

-   58. The use according to embodiments 42-55 or 56 wherein the    iontophoresis is cathodal and performed at a pH of at least about    7.5.

-   59. An iontophoretic system for the delivery of a compound through    skin, comprising (a) a transdermal delivery device attachable to the    skin, the device including a first electrode and a second electrode,    and a reservoir containing a compound of general formula I or a    formulation thereof and optionally a pharmaceutically acceptable    electrolyte in electrical communication with the first and second    electrodes and (b) means for connecting an electrical power source    to the first and second electrodes and (c) optionally a membrane    closing the reservoir.

-   60. The iontophoretic system of embodiment 59, wherein the compound    is rotigotine dihydrophosphate.

-   61. The iontophoretic system of embodiment 59, wherein the compound    is rotigotine orotate.

-   62. The iontophoretic system of embodiment 59, wherein the compound    is rotigotine hydrogen sulphate.

-   63. A method for the treatment or the prevention of CNS disorders    like Parkinson Disease, fybromyalgia, restless leg syndrome,    depression and/or Parkinson's accessory symptoms, characterised by    applying an iontophoretic device, which comprises a composition    comprising a compound of general formula I and optionally at least    one electrolyte, the composition having a pH of less than 6 with the    proviso that the compound of general formula I is not rotigotine    hydrochloride, onto the skin of a patient in need thereof.

-   64. A method for administering a pharmaceutically acceptable    rotigotine salt of formula I and/or formula (II) to a patient    comprising iontophoretically administering to the body surface of a    patient in need thereof, the formulation of any one of embodiments 1    to 27.

EXAMPLES

In order to compare the maximum solubility of pharmaceuticallyacceptable salts of rotigotine, e.g. rotigotine.H₃PO₄, withrotigotine.HCl, the solubility studies of rotigotine.salts were carriedout as described by Nugroho et al. (Pharm. Res. 21 (2004), 844-855),which is incorporated herein by reference, who determined the solubilityof rotigotine.HCl. Briefly, rotigotine.salt was solubilized in 10 mMcitric buffer at pH 4, 5 and 6 with and without the presence of NaCl (atroom temperature). Subsequent adjustment of pH in each test tube wasperformed by alternating adding small quantities of 1M NaOH undercontinuous shaking and subsequent pH measurements, until the pH of eachsolution had stabilized at the original buffer value. Each solution wasshaken for an additional 48 hours, after which each solution wascentrifuged and filtered. The concentration in each solution wasdetermined by HPLC. Room temperature or ambient as used in the presentapplication is to be understood to apply to a range from 18° C. to 25°C., preferred is about 20° C.

The preparation of human stratum corneum (HSC) was performed accordingto the method described previously (Nugroho et al., (Nugroho et al., J.Control Release (2005) 103, 393-403) which is incorporated herein byreference. Briefly, within 24 hours after surgical removal of the humanskin residual subcutaneous fat was removed. Dermatomed human skin (DHS)was obtained by dermatoming the skin to a thickness of about 300 μm. Inorder to obtain HSC, DHS was incubated with the dermal side on Whatmanpaper soaked in a solution of 0.1% trypsin in 150 mM phosphate bufferedsaline (PBS) pH 7.4 (NaCl: 8 g·L⁻¹, Na₂HPO₄: 2.86 g·L⁻¹, KH₂PO₄: 0.2g·L⁻¹, KCl: 0.19 g·L⁻¹) overnight at 4° C. and subsequently for 1 hourat 37° C. after which HSC was peeled off from the underlying viableepidermis and dermis. HSC was subsequently washed in a 0.1% trypsininhibitor solution in Millipore water and several times in water andstored in a desiccator in a N₂ environment.

The in vitro transport studies were done by using a 9-channel computercontrolled power supply in order to provide a constant direct current(Electronics Department, Gorlaeus Laboratories, Leiden University, TheNetherlands) during iontophoresis. The system was equipped withdifferential input channels per current source enabling on-linemeasurement of the electric resistance across HSC in each diffusioncell. Ag/AgCl was used as driver electrode pair. All transportexperiments were carried out, using a three chamber continuous flowthrough cell as described elsewhere (Nugroho et al., J. Control Release(2005) 103, 393-403). The donor formulation, buffered with a 10 mMcitric buffer, was applied at the anodal side. The cathodal chamber wasfilled with PBS pH 7.4. The acceptor phase, maintained at 32° C., wascontinuously perfused with PBS pH 6.2 (NaCl: 8 g·L⁻¹, KCl: 0.19 g·L⁻¹,Na₂HPO₄.2H₂O: 0.43 g·L⁻¹, KH₂PO₄: 0.97 g·L⁻¹) at a flow rate of 7.0ml·h⁻¹. Unless described elsewhere, the following protocol for theiontophoresis experiments was used: 6 hours of passive diffusion,followed by 9 hours of iontophoresis with a current density of 500μA·cm⁻² and 5 hours of passive diffusion. Samples were collected everyhour with an automatic fraction collector (ISCORetriever IV, Beun DeRonde BV, Abcoude, The Netherlands). The specific conditions of theindividual transport studies are described below.

Analytical Method

Prior to and at the end of a transport study the pH of donor andacceptor compartment was measured. All samples of the iontophoretictransport studies were analyzed by RP-HPLC using a Superspher® 60RP-select B, 75 mm-4 mm column (Merck KGaA, Darmstadt, Germany).Rotigotine was detected using a scanning fluorescence detector (Waters™474, Millipore, Milford, Mass., USA) at excitation and emissionwavelengths of 276 and 302 nm. Acetaminophen was detected using a UVdetector (Dual λ Absorbance Detector 2487, Waters, Milford, USA) at awavelength of 254 nm. Filtered and degassed mobile phase contained 60%H₂O (v/v), 40% ACN (v/v) and 0.05% methanesulfonic acid (v/v). Theinjection volume was 50 μL and the flow rate was set to 1.0 mL·min⁻¹.

The concentration of rotigotine was quantified according to 3 standardswith a concentration of 0.005, 2 and 5 μg·mL⁻¹. The intra-assayvariation of the retention time and of the area was less then 2.0%. Foracetaminophen, calibration curves showed a linear response when usingconcentrations of compounds between 0.1 and 40 μg·mL⁻¹ (r²>0.9999). Thelimit of detection (LOD) and limit of quantification (LOQ) ofacetaminophen were experimentally determined at 5.8 and 9.6 ng·mL⁻¹respectively. According to literature the limit of detection ofrotigotine (base) was 11 ng·mL⁻¹ ².

Data Analysis

To calculate the steady state flux during passive and iontophoretictransport, the cumulative flux of the transport was plotted as afunction of time. The steady state flux was estimated from the linearpart of the slope of this plot according to the permeation lag-timemethod⁷. All data are presented as mean±standard deviation (s.d.). Whena statistical analysis was performed comparing only 2 groups, a Studentst-test was used. When 3 or more groups were compared, a 1-way ANOVAstatistical analysis was executed. If the overall p-value was less than0.05, a bonferonni post-test was applied to compare different groups.For all statistical analysis a significance level of p<0.05 was used.

Example 1 Solubility of Rotigotine Hydrophosphate and RotigotineHydrochloride

The maximum solubilities of rotigotine hydrochloride (abbreviated asRo.HCl) and rotigotine hydrophosphate (abbreviated as rotigotine.H₃PO₄or Ro.H₃PO₄) have been investigated as a function of pH in a number ofsolvents (table.1). Ro.H₃PO₄ was dissolved in the indicated buffer uponwhich the pH of the formed solution was adjusted to the target value byaddition of sodium hydroxide solution. During addition rotigotineprecipitated indicating that saturation was achieved. The drug wasassayed by HPLC analysis in the filtered solution.

HPLC conditions:

-   Column: Merck Superspher 60 RP select B, length: 7.5 cm, column    internal diameter: 4 mm, particle size: 5 μm-   Mobile phase: 60% (v/v) water, 40% (v/v) acetonitrile 0.05% (v/v)    methanesulfonic acid-   Flow: 1.0 ml/min-   Injection volume: collected fractions: 50 μl, diluted donor    solutions: 4 μl-   Column temperature: ambient-   Detection: fluorescence, λ_(ex)=276 nm, λ_(em)=302 nm

TABLE1 The solubility of Rotigotine•H₃PO₄ and Rotigotine•HCl indifferent medium at pH 4, 5 and 6 in the presence and absence of 68 mMNaCl (n = 2-3). Solubility of Solubility of Rotigotine•H₃PO₄Rotigotine•HCl (μmol/ml) (μmol/m1) pH No NaCl 68 mM NaCl No NaCl 68 mMNaCl 4 83.48^(a) 80.08^(c) 24.39^(a, b) 6.75 5 41.89^(a) 42.95^(c)22.45^(a, b) 6.35 6 15.67 14.44^(d) 15.87^(b) 6.52 ^(a)p < 0.001; ^(b)p< 0.001; ^(c)p < 0.001; ^(d)P < 0.01 *the values were adapted fromreference (Nugroho et al.)

As shown in table 1, in the presence of NaCl in the donor formulation,the solubility of rotigotine increased substantially when HCl wasreplaced by H₃PO₄.

At the selected pH values the addition of NaCl did not affectsignificantly the solubility of rotigotine.H₃PO₄ (2-way ANOVA; p>0.05),which contrasted the results obtained with rotigotine.HCl by Nugroho.For rotigotine.HCl the solubility reduced tremendously after adding 68mM NaCl. The pH had a drastic influence on the solubility ofrotigotine.H₃PO₄. Decreasing the pH of the donor phase from 6 to 5 andagain to pH 4 resulted in a significant increase in the solubility ofrotigotine (2-way ANOVA; p<0.05). Compared to rotigotine.HCl thesolubility of rotigotine.H₃PO₄ is 2, 7, 12 fold higher at pH 6, 5 and 4,respectively. Furthermore in contrast to the solubility of the HCl-saltthe presence of NaCl did not affect the solubility of rotigotine.H₃PO₄.

Example 2 Iontophoresis Experiments

Many of the experiments were performed under the following testconditions—the standard conditions (If not stated otherwise these oneshave been used in the respective examples): Donor solvent: citratebuffer (10 mM citrate, see Table 2), 4 g/l NaCl and 23 g/l mannitol, pHas indicated per experiment.

TABLE 2 Concentrations for producing citrate buffers at the indicatedpH, other components, see above. Concentration (g/l) pH citric acid•H₂Otrisodium citrate•2 H₂O 5.0 0.73 1.94 5.5 0.46 2.30 6.0 0.24 2.60

Donor liquid preparation: a quantity of rotigotine.H₃PO₄ is dissolved inthe indicated donor solvent to produce a sufficient amount of donorliquid at the selected concentration. The pH of the formed solution isadjusted to the target value by addition of sodium hydroxyde solution.The solution is then filtered over a membrane filter (pore size: 0.45μm) and diluted with the same donor solvent as required to produce aconcentrated drug solution of the indicated concentration.

Acceptor liquid: PBS pH=6.2: 0.965 g/l KH₂PO₄, 0.425 g/l Na₂HPO₄.2H₂O, 8g/l NaCl, 0.19 g/l KCl

Kathode liquid: PBS pH=7.4, 0.19 g/l KH₂PO₄, 1.44 g/l Na₂HPO₄.2H₂O, 8g/l NaCl, 0.19 g/l KCl

Flow acceptor liquid: 6.5 ml/h

Temperature circulating water bath: 37° C.

Iontophoresis protocol: 6 hours: no current, 9 hours: 500 □A/cm², 5hours: no current.

Steady state flux calculation: the mean from flux values recorded withinthe time interval within which each flux value deviates not more than10% from that mean.

The iontophoresis cells used in the studies is a three compartment cell.A exemplarily design of cell is provided in FIG. 1.

The cell as shown in FIG. 1 consists of three compartments. An anodal (+electrode) and cathodal (− electrode) compartment in which the Ag andAgCl electrode, respectively, are located. In the donor (anodal)compartment the positively charged drug rotigotine is dissolved in thebuffer solution. In between the anodal and cathodal compartment a thirdcompartment is located. During an iontophoresis experiment a constantflow of buffer is transport across this compartment simulating the bloodflow in vivo. On both sides of the central compartment human skin isclamped (between anodal-acceptor compartments and cathodal-acceptorcompartments). The skin is clamped in such a way the inner part of theskin or stratum corneum is facing the acceptor compartment. In this waythe in vivo situation is closely simulated.

Some of these conditions were varied in the experiments in order tostudy the impact of their variation on the drug flux.

As stated below a series of iontophoretic transport studies undervarious conditions were performed to investigate the iontophoreticdelivery of rotigotine.H₃PO₄. During 6 hours prior to iontophoresis nocurrent was applied and passive transport of rotigotine was observed,which reached steady state conditions within this period of 6 hours.From the slope of the linear part of the cumulative flux vs time profilethe passive steady state (Flux_(pss)) was calculated. The influence ofthe pH of the donor solution on the passive transport ofrotigotine.H₃PO₄ was investigated. The results of transport studies atvarious donor concentrations, comparing a donor pH of 5 and 6 aredepicted in FIG. 4. A non-linear hyperbolic fit showed a correlationbetween the Flux_(pss) and the donor concentration for pH 5 (R²=0.889).Increasing the pH of the donor phase from 5 to 6 increased the passiveflux of rotigotine.H₃PO₄ quite drastically: Close to saturation ofrotogotine.H₃PO₄ in the donor phase the maximum flux that could beachieved was 10.8±1.9 nmol·cm⁻²·h⁻¹ at pH 5 and 24.9 nmol·cm⁻²·h⁻¹±2.5at pH 6.

A series of iontophoretic transport studies was conducted to investigatethe iontophoretic transport of rotigotine.H₃PO₄ under various conditionsspecially focusing on (i) the relationship between the flux and donorconcentration, (ii) the influence of the pH, (iii) the determination ofthe transport number, (iv) impact of current density, (v) impact ofchloride salt, (vi) in vivo simulation.

(i) Impact of Donor Concentration

In these transport studies 4 different concentrations rotigotine.H₃PO₄(4.4 mM, 9.5 mM, 22.2 mM and 47.5 mM (corresponding to concentrationsrotigotine free base of 1.4 mg/ml, 3 mg/l, 7 mg/ml and 15 mg/ml),buffered at pH 5, were used. All transport experiments were performed inthe presence of 68 mM NaCl in the donor phase.

TABLE 3 Drug concentration in donor phase versus steady state fluxvalues, conditions: pH = 5.0, other conditions, see text. Rotigotinefree base conc. Mean steady state flux ± sd (mg/ml) (μg/cm²/h) 1.4 22.1± 2.5  3 26.0 ± 2.1  7 37.7 ± 1.5  15 41.5 ± 3.4  Note: mean values from4 experiments, concentrations in this table are nominal, actual assayeddrug concentration vary per experiment.

The highest drug concentrations in this graph of FIG. 2 represent 80% ofthe maximum solubility of rotigotine.H₃PO₄ at pH=5.0.

The linear relationship between drug concentration in the range 0.5 to1.4 mg/ml and steady state flux observed earlier for rotigotine.HCl isno longer present in the higher concentrated range between 1.4 and 15mg/ml. Instead, increasing drug concentration from 7 to 15 mg/mlincreases the flux only from 38 to 41 μg/cm²/h.

As shown in FIG. 3, current application results in an immediate increasein the flux of rotigotine.H₃PO₄, which reaches steady state within fourhours. The results of a series of iontophoretic transport studies ofdifferent concentrations rotigotine.H₃PO₄ varying from 4.4 mM to 47.5 mMat pH 5 and 4.4, 13.5 mM (millimolar) at pH 6 are depicted in FIGS. 2and 4. A non-linear relationship can be described between the Flux_(ss)and the donor concentration at pH 5 (R²=0.825). Thereby the Flux_(ss) atequal rotigotine.H₃PO₄ concentration increases with increasing pH of thedonor solution.

(ii) Impact of pH

Further to the under (i) mentioned transport studies at 4 differentconcentrations rotigotine.H₃PO₄ (4.4 mM, 9.5 mM, 22.2 mM and 47.5 mM),buffered at pH 5, the transport of rotigotine.H₃PO₄ (4.4 and 13.0 mM),buffered at pH 6 was investigated as well. All transport experimentswere performed in the presence of 68 mM NaCl in the donor phase.

However, when comparing the Flux_(ss) at pH 5 and 6 close to saturationin the donor phase, the Flux_(ss) values are very similar as shown inFIG. 4.

Experiments have been performed to study the effect of pH and donorconcentration on both passive and iontophoretic drug flux. Acceptorsolvent pH (=6.2) is the same for all experiments. The table 4 and FIG.5 summarise the impact of pH and drug concentration on steady state fluxof rotigotine during the passive and active stage of a number ofexperiments.

TABLE 4 Impact of pH value donor solution on passive and iontophoretictransdermal rotigotine flux (calculated as free base). rotigotine freebase donor conc. ± s.d. steady state flux ± s.d. (μg/cm²/h) pH (mg/ml)passive stage iontophoresis stage 5.0 1.28 ± 0.03 0.5 ± 0.2 20.0 ± 4.9 1.46 ± 0.04 0.9 ± 0.3 22.1 ± 2.5  3.11 ± 0.16 1.0 ± 0.1 26.0 ± 2.1  6.95± 0.23 2.3 ± 0.5 33.7 ± 4.7  15.09 ± 0.30  3.6 ± 0.5 41.5 ± 3.4  5.59.88 7.7 ± 0.5 47.9 ± 3.1  6.0 1.24 4.1 ± 1.9 26.4 ± 1.3  1.42 3.2 ± 0.225.1 ± 3.3  4.13 ± 0.14 9.3 ± 0.9 43.0 ± 2.6  4.3  12.3 ± 0.9  47.1 ±1.8 

As can bee seen the highest tested rotigotine concentrations at pH 5.0,5.5 and 6.0 are approximately 4, 10 and 15 mg/ml, which is 90% (pH=5.0and 5.5) or 80% (pH=6.0) of the maximum solubility of the acid additionsalt of rotigotine, e.g. rotigotine.H₃PO₄ at that pH value.

(iii) Determination of Transport Number

In a single experiment the relationship between the Flux and the currentdensity was studied with a donor solution, buffered at pH 5.5,containing 31.3 mM rotigotine.H₃PO₄ in the presence of 68 mM NaCl. Thefollowing protocol was used: 6 h passive+6 h 166 μA·cm⁻²+6 h 333μA·cm⁻²+6 h 500 μA·cm⁻²+6 h passive. The donor concentration was 90% ofthe maximum solubility of rotigotine.H₃PO₄ under these conditions. Anincrease in the current density resulted in a significant increase influx, which reached steady state within 6 hours of current application.A current density of 0 μA·cm⁻² (passive phase), 166 μA·cm⁻², 333 μA·cm⁻²and 500 μA·cm⁻² resulted in a Flux_(ss) of 24.4±1.9 nmol·cm⁻²·h⁻¹,65.8±9.3 nmol·cm⁻²·h⁻¹, 109.7±15.7 nmol·cm⁻²·h⁻¹ and 154.5±27.0nmol·cm·h⁻¹, respectively. An excellent linear correlation could beobserved between the Flux_(ss) and the current density (R²=0.999) andthe transport number was calculated from the slope of the correlation at0.7%. The transport number of rotigotine.H₃PO₄ at pH 5.5 in the presenceof 68 mM NaCl was estimated from the slope of relationship between theFlux_(ss) and the current density at 0.7%, which is higher than thetransport number of rotigotine.HCl (0.4%) at pH 5, which can beexplained by a higher donor concentration of rotigotine.H₃PO₄

(iv) Impact of Current Density

The current density was varied over the time of the experiment accordingto the following: 0-6 hours: no current; 6-12 hours: 167 μA/cm²; 12-18hours: 333 μA/cm²; 18-24 hours: 500 μA/cm²; 24-30 hours: no current.

Protocol a: The impact of iontophoretic current density on the drugsteady state flux has been examined with drug donor concentration(calculated as free base) 7 mg/ml and pH=5.0. Per experiment threecurrent density values were tested with two cells per current value.

Protocol b: The impact of iontophoretic current density on the drugsteady state flux has been examined at pH=5.5, drug donor concentration(calculated as free base): 9.9 mg/ml (31.3 mM) (=90% of maximumsolubility at pH=5.5). Per experiment three current density values weretested with two cells per current value. Results are summarised in Table5.

TABLE 5 Iontophoretic steady state flux at various current densityvalues, drug conc.: 7 mg/ml (protocol a) and 9.9 mg/ml (protocol b).current density rotigotine flux_(ss) ± sd (μg/cm²/h) (μA/cm²) Protocol 1(pH = 5.0) Protocol 2 (pH = 5.5) 167 12.3 ± 0.3  20.2 ± 2.3  333 21.0 ±1.1  33.8 ± 2.9  500 29.7 ± 0.5  47.7 ± 3.1 

From these results as shown in FIG. 6 it can be concluded that there isa linear relationship between applied current density and transdermalrotigotine flux at both pH values and concentration levels. Also with nocurrent switched on there is a drug flux which represents the passivediffusion level. Changing the current density rapidly changes therotigotine flux in a predictable way and therefore the flux can beadjusted to the requirements of the individual patient.

The relationship between the current density was further studied with arotigotine.H₃PO₄ concentration of 31.3 mM, buffered with a citric bufferat pH 5.5, containing 68 mM NaCl. The following protocol was used: 6 hpassive+6 h 166 μA·cm⁻²+6 h 333 μA·cm⁻²+6 h 500 μA·cm⁻²+6 h passive.

(v) Impact of Sodium Chloride

As shown by table 1 sodium chloride has no negative impact on rotigotinephosphate solubility and can thus be added to the donor solution to feedthe electrochemical reaction at the anodal side.

(vi) In Vivo Simulation

After characterizing and optimizing the transdermal delivery of thispromising compound in vitro, the potential of the iontophoretic deliveryof rotigotine in vivo was evaluated in a series of simulations, usingpharmacokinetic modeling. The first step was to determine the parametersdriving the iontophoretic delivery in vitro across human stratum corneumof rotigotine.H₃PO₄ (47 mM), buffered at pH 5. The value of theFlux_(ss) corresponds well with the value estimated by the permeationlag time method. In addition diagnostic plots of the data modelingconfirm that this model successfully describes the in vitroiontophoretic transport of rotigotine.H₃PO₄. In the next step theapparent pharmacokinetic parameters of rotigotine reported inliterature, are combined with the best-fit values of Flux_(ss), K_(R)and t_(L) to predict the plasma levels in vivo. For these simulations 2different protocols were used to evaluate the iontophoretic delivery ofrotigotine (47 mM, pH 5) during 24 h and a comparison was made with thepassive delivery of rotigotine. As found in literature, passive deliveryof rotigotine with a patch size of 10 cm², estimated to deliver 2 mg in24 h, resulted in a maximum plasma concentration (C_(max)) of 215pg·ml⁻¹ at 16 h²¹. As shown in FIG. 7 applying a current density of 350μA·cm⁻² during 24 h (protocol 1) is expected to result in C_(max) of 630pg·ml⁻¹. Not only can a higher flux be established with iontophoresis,but more interestingly already at time=5 h a plasma concentration of 240pg·ml⁻¹ can be reached. Therefore the in vivo iontophoretic delivery ofrotigotine was simulated using protocol 2, applying initially a currentdensity of 350 pA·cm⁻² for 5 h, after which the current density wasdecreased to 150 pA·cm⁻² resulting in a steady state plasmaconcentration during 19 h. These simulations demonstrate two veryimportant benefits of iontophoretic delivery of rotigotine incombination with iontophoresis over transdermal passive diffusion forsymptomatic treatment of Parkinson's disease. Because of activetransdermal delivery the onset time to achieve the desired level can besignificantly decreased. Secondly by adjusting the current density atitration of the plasma concentration is possible, making it feasible toindividually modulate the delivery according to the desired dosingregimen.

CONCLUSION

One advantage is the increase in solubility of rotigotine.H₃PO₄ comparedto that of rotigotine.HCl, which results in an increase in the maximumiontophoretic transport. At pH 5 the latter resulted in a maximumiontophoretic flux of 80.2±14.4 nmol·cm⁻²·h⁻¹, while withrotigotine.H₃PO₄ a maximum flux of 135.8±12.5 nmol·cm⁻²·h⁻¹ wasachieved. This means that the maximum flux can be increased with 170% byreplacing the HCl salt by H₃PO₄. Besides a higher flux another practicaladvantage can be established when using a high donor concentration at pH5. Calculations revealed that after 24 h, maintaining a maximum flux of135.8 nmol·cm⁻²·h⁻¹, the amount rotigotine.H₃PO₄ in the donor phasedecreased with 35%. This decrease in donor concentration would resultonly in a decrease of 10% in steady state flux, showing that with a highdonor concentration a high flux can be maintained for a long time.Taking these results together, preferably one should seek a balancebetween transport efficiency and donor concentration by choosing the pHof the donor solution. On one hand by increasing the pH it is possibleto increase the transport efficiency, however the limited solubility ofthe compound at pH 6 prevents the use of a high concentration. On theother hand at pH 5 the transport efficiency is lower, nonetheless a highflux can be established for a long time due to the higher solubility ofrotigotine.H₃PO₄.

It is clear from the data obtained that rotigotine iontophoresis usingrotigotine acid addition salts, in particular rotigotine dihydrogenphosphate, providing a higher saturation solubility of the salt in anaqueous solution than 16 μmol/ml at a pH less than 6 and/or a saturationsolubility in an aqueous solution of at least 30 μmol/ml pH wherein allthe above saturation solubilities are calculated based on the totalamount of rotigotine in the pharmaceutically acceptable acid additionsalt, is promising.

Fluxes of around 50 μg/cm²/hr can be achieved. A linear relationshipbetween iontophoresis (steady state flux) and current density wasobtained, which allows individual dose titration into the patient.

Example 3 General Procedure for Preparation of Rotigotine Acid AdditionSalt

Rotigotine free base (6 g) was dissolved in isopropanol (IPA) (24 ml, 4volumes) at ambient (app. 20° C.) and 800 μl was charged to a vial whichwere capped and stood at ambient for 1.5 hours. The solutions wereheated to 60° C. and the acid was added as stock solutions (1 eq. in H₂Oor THF depending on solubility). The reaction mixtures were stirred atelevated temperature for 10 minutes and then cooled slowly to ambient.After 2 hours at ambient the reaction mixtures solutions were stored at4° C. for 16 hours.

Rotigotine Dihydrogen Phosphate Salt (LJC-028-037-1)

Rotigotine free base (500 mg, 1.58×10⁻³ mol) was charged to a 5 ml roundbottomed flask and IPA (1.5 ml, 3 volt) added at ambient. To thesolution H₃PO₄ (171 mg, 1.1 eq.) was charged as solid and immediately anagglomeration of white material formed. The reaction mixture was stirredfor 30 minute at ambient and sonicated in order to break up the ball ofmaterial. The powder was stirred for one hour and the solid was filteredand washed. The solid began to deliquesce, so was plunged back into thefiltrates, and H₂O, (75 μl) was added. The reaction mixture was heatedto 55° C., held for 15 minutes and cooled to ambient. After 12 daysstanding at ambient without stirring, the yellow solution was decantedfrom the gum and concentrated under vacuum to yield a white/off-whitesolid. The material was oven dried at 40° C. under vacuum for 2 hours. Ayield of 525 mg was obtained as an amorphous solid and analyzed by XRPD(FIG. 8). The diffractogram can not be defined as reference, because itis amorphous. It is important to realize that in a non-crystallinesample, molecules within that sample would be in random orientations andtherefore would have a continuous Fourier spectrum that spreads itsamplitude more uniformly and with a much reduced intensity and moreimportantly, the orientational information is lost. In the crystal, themolecules adopt the same orientation within the crystal, whereas in aliquid, powder or amorphous state, the observed signal is averaged overthe possible orientations of the molecules. Therefore the salt wasfurther characterized by ¹H NMR (FIG. 9) (comprising small amounts ofIPA and ultimate analysis (elementary analysis). Carbon and Hydrogencontent have been determined by according to DIN51721; phosphor andsulphur have been determined according to DIN EN 1189 (photometric): C51.3%, H 6.96%, S 6.75%, P 8.17%, all results correspond to calculation.DSC did not provided a clear signal.

Rotigotine Dihydrogen Citrate Salt (LJC-028-037-2)

Citric acid (1.74 ml, 1 equ, 1 M in THF) was charged to a 5 ml roundbottomed flask and rotigotine free base (500 mg, 1.58 mg×10⁻³ mol) wasadded in portions. An orange agglomeration of material formed whichprevented stirring. After manual shaking most of the gelatinous materialhad dissolved in the THF, but stirring was still difficult. H₂O (87 μA)was added, and the reaction mixture was heated to 50° C. for 5 minutes,then slowly cooled to 40°. At this temperature heptane (5×200 μl) wasadded and no cloud point was obtained, so the reaction mixture wascooled to ambient. An oily gum formed after 16 hours, which wastriturated with Et₂O and stored at −20° C. for a further 16 hours. Thesolvent was decanted and the gum brought to ambient then tritiurationwas carried out with n-heptane, n-pentane, MtBE and Et₂O. Solid did notmaterialise. The gum was stood at ambient for 9 days and it slowly beganto solidify as an amorphous solid and analyzed by XRPD (FIG. 10) Thesalt was further characterized by 1H NMR (FIG. 11).

Rotigotine Hydrogen L-tartrate Salt (LJC-028-050-1)

Rotigotine free base (100 mg, 3.17×10−4 mol) was charged to a vial andIPA (300 μl, 3 vol) was added at ambient. The solution was then heatedto 60° C. and L-tartaric acid (630 μl, 1M, in THF) was added and thesolution held at the elevated temperature for 10 minutes. The heat wasremoved and the solution cooled slowly. No precipitate had formed so thesolution was stored at 4° C. for 16 hours. After 10 days the solutionwas concentrated under vacuum to an oil which was triturated with Et₂O.The oil solidified and was confirmed as the tartrate salt by ¹H NMR(FIG. 12).

Rotigotine Orotate Salt (LJC-028-045-2)

Rotigotine free base (1.0 g, 3.170×10−3 mol) was charged to a 25 mlround bottomed flask and IPA (4 ml) added. The reaction mixture wasstirred until all solid had dissolved and orotic acid (490 mg, 1 equ)was added as a solid. The suspension was stirred at ambient for 10minutes and then heated to 75° C. Some material had dissolved, but itwas not a complete solution. After 10 minutes at 75° C., the heat wasturned off and the reaction mixture cooled slowly at 10° C. an hour.Once at 55° C., the reaction mixture was aged for 16 hours. The reactionmixture was then cooled to ambient, where a mixture of powder and veryhard solid was present. The powder was filtered and the hard materialwas manually broken up then filtered. The solid was washed in IPA anddried at 40° C. under vacuum. ¹H NMR confirmed the orotate salt (FIG.13).

This orotate salt (≈75 mg) was charged to a vial and slurried in iPrOAc(10 vol) on a double heat/cool cycle from 25° C. to 50° C. The vial wasshaken over the 48 hour period and then filtered, washed and dried at40° C. under vacuum. XRPD confirmed crystalline material (FIG. 14).

Rotigotine 1-hydroxy-2-naphtoate salt (LJC-028-020-1)

Rotigotine free base (100 mg, 3.17×10−4 mol) was charged to a vial IPA300 μl, 3 vol) was added at ambient. The solution was then heated to 60°C. and 1-hydroxy-2-napthoic acid (1M, 630 μl, in THF) was added and thesolution held at the elevated temperature for 10 minutes. The heat wasremoved and the solution cooled slowly. No precipitate had formed so thesolution was stored at 4° C. for 16 hours. After 10 days the solutionwas concentrated under vacuum to an oil which was triturated with Et₂O.The oil was very miscible with the Et₂O. The solvent was evaporated andthe oil was stores at 4° C. for 5 days after which time it hadcrystallised. The salt was confirmed as the 1-hydroxy-2-napthoate by ¹HNMR and confirmed to be crystalline by XRPD (FIG. 15, 16) and DSC with apeak at 176.37 (FIG. 17).

Rotigotine Hydrogen Sulphate Salt (LJC-028-007-2)

Rotigotine free base (100 mg,) was charged to a vial as a stock solutionin IPA (1 ml) and stock sulphuric acid (1 equ, 1M in THF) was added atambient. The reaction mixture was stirred for 8 hours after which time aprecipitate had formed. This was filtered, washed and dried at 40° C.under vacuum. XRPD confirmed the salt to be amorphous (FIG. 18). ¹H NMRconfirmed the salt due to significant peak shifts (FIG. 19).

Example 4

Rotigotine has both a basic and acidic group. Therefore the saltformation by using bases as well was done. Due to the high pKa valueonly three bases were suitable: NaOH, KOH and L-arginine (pKa=14 forhydroxides, 13.2 for L-arginine). The experimental procedures aredescribed below.

Rotigotine Sodium Salt (LJC-028-053-1)

NaOH (0.95M in IPA/H₂O, 3:1) was charged to a round bottomed flask andstirred at ambient. SPM 962 (200 mg in 600 μl) was added to the NaOHsolution and an oil formed instantly. The reaction mixture was stirredat ambient for 16 hours and a pink oil was present. After a total of 72hours at ambient the oil was concentrated under vacuum, then treated ona high vacuum line. The oil had begun to solidify after 16 hours. ¹H NMRconfirmed salt by significant peak shifts in the spectrum (FIG. 20).

Analytical Methods Nuclear Magnetic Resonance Spectroscopy (NMR)

All spectra were collected on a Bruker AVANCE 400 MHz Spectrometer inDMSO.

X-ray Powder Diffraction (XRPD)

X-ray powder diffraction was carried out on a Bruker C2 diffractometerequipped with an XYZ stage and laser video microscope for auto-samplepositioning; and a HiStar area Detector with typical collection times of120 s. The sealed copper tube (Cu Ka radiation; 1.5406 Å) voltage andamperage were set at 40 kV and 40 mA. The X-ray optics on the C2consists of a single Göbel mirror coupled with a pinhole collimator of0.3 mm.

Beam divergence i.e., effective size of X-ray spot, gives a value ofapproximately 4 mm. Theta-theta continuous scans were employed with asample—detector distance of 20 cm which gives an effective 20 range of3.2-29.8°. A corundum (α-Al₂O₃) standard (NIST 1976 flat plate) was runmonthly to check the instrument calibration.

Sample preparation consisted of 1-2 mg of sample pressed lightly on aglass slide to obtain a flat surface.

Differential Scanning Calorimetry (DSC)

DSC data was collected on a TA instruments Q1000. The energy andtemperature calibration standard was indium. Samples were heated at arate of 10° C./min, in a nitrogen atmosphere (30 mL/min purge rate) inopen aluminium pans unless otherwise stated.

1. A pharmaceutical formulation comprising at least one pharmaceuticallyacceptable acid addition salt of6-(propyl-(2-thiophen-2-ylethyl)amino)tetralin-1-ol (rotigotine) andoptionally a pharmaceutically acceptable electrolyte wherein saidrotigotine salt has a saturation solubility in an aqueous solution whichis at least 16 μmol/ml at a pH<6 and/or of at least 30 μmol/ml at apH≦5, wherein all the above saturation solubilities are calculated basedon the total amount of rotigotine in the pharmaceutically acceptableacid addition salt with the proviso that said salt is notrotigotine.HCl.
 2. The pharmaceutical formulation according to claim 1,wherein the electrolyte is a chloride salt.
 3. The pharmaceuticalformulation according to claim 2, wherein the concentration of thechloride salt is about 1 to 140 mmol/1.
 4. The pharmaceuticalformulation according to claim 1, wherein the pH of the pharmaceuticalformulation is ≦5.
 5. The pharmaceutical formulation according to claim1, wherein the saturation solubility in an aqueous solution is providedat about 18-25° C.
 6. The pharmaceutical formulation according claim 1,wherein the pharmaceutical formulation comprises the at least onepharmaceutically acceptable salt of rotigotine in an amount of at lessthan 100% of the amount necessary to achieve saturation.
 7. Thepharmaceutical formulation according to claim 1, wherein the at leastone pharmaceutically acceptable acid addition salt of rotigotine isselected from the group consisting of dirotigotine hydrogen phosphate,rotigotine dihydrogen phosphate, rotigotine dihydrogen citrate,dirotigotine hydrogen citrate, rotigotine orotate, rotigotine1-hydroxy-2-naphtoate, rotigotine hydrogen sulfate, rotigotine sulphate,and rotigotine hydrogen tartrate.
 8. The pharmaceutical formulationaccording to claim 1, wherein the at least one pharmaceuticallyacceptable acid addition salt of rotigotine is rotigotine dihydrogenphosphate.
 9. (canceled)
 10. (canceled)
 11. A method for preventing ortreating a CNS disorder selected from the group consisting ofParkinson's disease, Restless Legs Syndrome, Parkinson Plus Syndrome,depression, fibromyalgia and Parkinson's accessory symptoms in asubject, the method comprising administering to the subject apharmaceutical formulation comprising at least one pharmaceuticallyacceptable acid addition salt of6-(propyl-(2-thiophen-2-ylethyl)amino)tetralin-1-ol (rotigotine) andoptionally a pharmaceutically acceptable electrolyte wherein saidrotigotine salt has a saturation solubility in an aqueous solution whichis at least 16 μmol/ml at a pH<6 and/or of at least 30 μmol/ml at apH≦5, wherein all the above saturation solubilities are calculated basedon the total amount of rotigotine in the pharmaceutically acceptableacid addition salt with the proviso that said salt is notrotigotine.HCl.
 12. A compound corresponding in structure to Formula I:

wherein X^(n−) is the acid anion of a pharmaceutically acceptableinorganic or organic acid and wherein n is 1-5 with the proviso that itis not rotigotine.HCl.
 13. The compound according to claim 12, with thefurther proviso that formula I is not(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-olhydrobromide,(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-olp-toluensulfonate,(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-olheminaphthalene-1,5-disulfonate,(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-oltartrate,(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-olcitrate, rotigotine methane sulphonic acid or(S)-6-(propyl(2-thiophen-2-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-1-olphosphate.
 14. The compound according to claim 12, wherein the X^(n−) isselected from the acid anion of phosphoric acid, sulphuric acid, oroticacid, 1-hydroxy-naphtoic acid, citric acid and tartaric acid.
 15. Acompound corresponding in structure to Formula II:

wherein M⁺ is selected from the group consisting of Na⁺, K⁺ andarginate.
 16. A method for preventing or treating a CNS disorderselected from the group consisting of Parkinson's disease, Restless LegsSyndrome, Parkinson Plus Syndrome, depression, fibromyalgia andParkinson's accessory symptoms in a subject, the method comprisingadministering to the subject a compound corresponding in structure toFormula II:

wherein M⁺ is selected from the group consisting of Na⁺, K⁺ andarginate.
 17. The method according to claim 16, wherein the compoundcorresponding in structure to Formula II is administered to the subjectby a transdermal delivery system.
 18. The method according to claim 17,wherein the transdermal delivery system is an iontophoretic system. 19.The method according to claim 18, wherein the iontophoretic systemcomprises an iontophoretic device capable of delivering a currentdensity at a level from about 0.001 to about 1.0 mA/cm².
 20. The methodaccording to claim 22, wherein the compound of formula I is selectedfrom the group consisting of rotigotine dihydrophosphate, rotigotineorotate, rotigotine hydrogen sulphate, rotigotine hydrogen tartrate, androtigotine dihydrogen citrate.
 21. The compound according to claim 14,wherein the X^(n−) is selected from the acid anion of phosphoric acid,sulphuric acid, orotic acid, 1-hydroxy-naphtoic acid, citric acid andtartaric acid, and the compound of formula I is rotigotine dihydrogenphosphate.
 22. A method for preventing or treating a CNS disorderselected from the group consisting of Parkinson's disease, Restless LegsSyndrome, Parkinson Plus Syndrome, depression, fibromyalgia andParkinson's accessory symptoms in a subject, the method comprisingadministering to the subject a compound corresponding in structure toFormula I:

wherein X^(n−) is the acid anion of a pharmaceutically acceptableinorganic or organic acid and wherein n is 1-5 with the proviso that itis not rotigotine.HCl.
 23. The method according to claim 22, wherein thecompound corresponding in structure to Formula I is administered to thesubject by a transdermal delivery system.
 24. The method according toclaim 23, wherein the transdermal delivery system is an iontophoreticsystem.
 25. The method according to claim 24, wherein the iontophoreticsystem comprises an iontophoretic device capable of delivering a currentdensity at a level from about 0.001 to about 1.0 mA/cm².
 26. The methodaccording to claim 11, wherein the pharmaceutical formulation isadministered to the subject by a transdermal delivery system.
 27. Themethod according to claim 26, wherein the transdermal delivery system isan iontophoretic system.
 28. The method according to claim 27, whereinthe iontophoretic system comprises a device capable of delivering acurrent density at a level from about 0.001 to about 1.0 mA/cm².